It is important to understand how the different functional groups react with each other in the synthesis. Among these functional groups, ketones and aldehydes are known to be two of the most important functional groups.
Ketones are called carbonyl groups and aldehydes are called formyl groups. What they have in common is that they both have a C=O structure. Therefore, in organic chemistry, both carbonyl and formyl groups undergo similar chemical reactions.
Carbonyl compounds, including ketones and aldehydes, cause various types of chemical reactions. They are very important functional groups in organic chemistry because they can synthesize many compounds.
However, there are many types of reactions and their reactions tend to be complex. In this section, we will explain the nucleophilic addition to carbonyl compounds, which is one of the most common chemical reactions of carbonyl compounds.
Table of Contents
- 1 Carbon Atoms in Carbonyl Compounds Are Electron Deficient
- 2 Nucleophilic Addition Reaction of Carbonyl Compounds
- 3 Carbonyl Compounds Have Many Types of Synthesis
Carbon Atoms in Carbonyl Compounds Are Electron Deficient
Organic chemistry deals with a variety of functional groups. Among these functional groups, carbonyl compounds have one thing that is unique. That is, the carbons in carbonyl compounds are electron-deficient.
In the case of carbonyl and formyl groups, there is an oxygen atom attached to the carbon atom. And they’re not connected by a single bond, but by a double bond. Therefore, electrons in the double bond can be transferred to the oxygen atom.
The carbon atom is positively charged and is connected to the oxygen atom by a double bond, making it easier for the nucleophile to attack the carbon atom. This is a fact that we must recognize in synthetic reactions with carbonyl compounds.
In the Absence of Leaving Groups, Nucleophilic Addition Reaction Occurs
In the case of carbonyl and formyl groups, there are no leaving groups. For ketones, next to the carbon atom of C=O is an alkyl chain. For aldehydes, too, the alkyl chain and the hydrogen atom are next to the C=O carbon atom. Therefore, carbonyl and formyl groups are subject to nucleophilic addition reactions.
The reaction proceeds as the nucleophile (Nu) attacks the carbonyl carbon, as shown below.
After the nucleophilic agent attacks the carbonyl carbon, the carbon atoms form sp3 hybrid orbitals (tetrahedra). The intermediates formed in this process are called tetrahedral intermediates. Tetrahedral intermediates are always produced when the nucleophile attacks the carbonyl carbon.
However, the state of the oxygen atom with a negative charge is unstable. Therefore, the oxygen atom attacks the hydrogen atom (proton) to form -OH. In this way, the synthetic reaction is completed.
Nucleophilic Acyl Substitution Reactions in the Presence of Leaving Groups
There are many types of carbonyl compounds. The carbonyl and formyl groups do not have any leaving groups. On the other hand, for example, the following compounds are known to be carbonyl compounds with C=O structure.
- Carboxylic acid
- Acyl halide
- Acid anhydride
These compounds are called carboxylic acid derivatives. Unlike carbonyl groups, these carboxylic acid derivatives are not linked together by alkyl chains, but instead have an oxygen atom, nitrogen atom, or other atoms with high electronegativity attached to a carbon atom.
In the case of these carboxylic acid derivatives, substitution reactions occur because of the presence of highly electronegative atoms next to the carbon atom. The following nucleophilic acyl substitution reactions occur.
Nucleophilic addition reactions do not occur, as they do with carbonyl and formyl groups. The type of chemical reaction that occurs depends on the presence of the leaving group.
Nucleophilic Addition Reaction of Carbonyl Compounds
In the reactions of carbonyl compounds, if we explain even the contents of carboxylic acid derivatives, the content of the reactions would be very extensive. Therefore, we will explain the nucleophilic addition reactions between carbonyl and formyl groups, in which there are no leaving groups.
There are several types of nucleophilic addition reactions to ketones and aldehydes. Among them, the most important synthetic reactions are as follows
- Grignard reaction
- Synthesis of cyanohydrin
- Synthesis of Amines: Imine and Enamine
- Hydration reaction: acetal and hemiacetal
The reagents used are different, and the compounds produced are different. However, the reaction mechanisms are all nucleophilic additions to carbonyl compounds. The following is an explanation of how the synthetic reactions are carried out for ketones and aldehydes.
Synthesis with Grignard Reagent
A very strong basic compound is an organometallic compound. Organometallic compounds react with carbonyl and formyl groups to form hydroxy groups (-OH).
There are different types of organometallic compounds, the most famous compound is the Grignard reagent. Compounds with magnesium (Mg) in the molecule are Grignard reagents, and the Grignard reaction results in a nucleophilic addition reaction. A compound with the following structure is a Grignard reagent.
In Grignard reagent, the carbon atom bound to magnesium has a negative charge. Therefore, the synthesis proceeds in the same way as carbanions (negatively charged carbon atoms).
What is the reaction mechanism of the Grignard reaction? In this regard, the anionic carbon of the Grignard reagent attacks the carbonyl carbon. At the same time, an oxygen atom and a magnesium atom are bound to it. The result is as follows.
Tetrahedral intermediates, in which the oxygen atoms are negatively charged, are unstable. However, since organometallic compounds are extremely basic, they can exist as tetrahedral intermediates.
Subsequent treatment, for example, by adding water, causes the magnesium atoms to disappear from the oxygen atoms and the hydrogen atoms to bond to the oxygen atoms. The result is the synthesis of alcohol.
Grignard reactions to ketones and aldehydes can be used to make new carbon chains. Therefore, it is one of the most important synthetic reactions in organic chemistry.
Synthesis of Cyanohydrin in the Presence of Proton
The carbonyl carbons are subject to nucleophilic attack, even if they are not strong bases, such as organometallic compounds. Cyanide ions, for example, are known to be nucleophiles.
The synthesis of cyanohydrin uses HCN (hydrogen cyanide) in the reaction. After the cyanide ion attacks the carbonyl carbons, the oxygen atoms capture the hydrogen atoms (protons) present in the solution. The result is the formation of cyanohydrin.
The important thing is the presence of a proton in the solution. If the reaction is not carried out with a strong base and there is no H+ present in the solution, the cyanide ion will become a leaving group and return to its previous state.
Cyanohydrin can be synthesized only because of the presence of protons in solution, since cyano groups have the ability to leave.
Reaction by Amines to Imine or Enamine
Amines are compounds that react with ketones and aldehydes by a reaction mechanism similar to that of cyanide ions, as explained earlier. As shown below, amines are classified into primary, secondary, and tertiary amines depending on the number of carbon chains to which they are attached.
For these amines, the addition of H+ to the solution leads to the following reactions, as well as the cyanide ion.
The compound that is formed is called hemiaminal. The difference from the cyanohydrin synthesis just described is that the nitrogen atoms are positively charged after the amine attacks. Therefore, in primary and secondary amines, the protons are removed, and the positive charge disappears.
Tertiary amines, on the other hand, have no protons to be removed. Amines with a positive charge are excellent leavening groups, so even if a tertiary amine attacks the carbonyl carbon, it will be restored, as shown below.
In other words, when tertiary amines react with a carbonyl compound, the synthetic reaction does not proceed. The reaction of carbonyl compounds with primary or secondary amines is what allows the carbonyl compounds to proceed with their synthesis.
-Primary Amines React with Ketones and Aldehydes to Form Imines
Unlike the Grignard reaction and cyanohydrin synthesis, the next reaction proceeds. This is because the product compound, hemiaminal, is an unstable substance.
When a primary amine reacts with a ketone or aldehyde, the hemiaminal yields an imine. The reaction mechanism is as follows.
In the formation of imine, imine is made by the formation of a double bond between a nitrogen atom and a carbon atom. Due to the presence of a hydrogen atom in the nitrogen atom, the double bond is formed as soon as the H+ disappears.
-Secondary Amines React with Ketone or Aldehyde to Become Enamine
On the other hand, what happens when a secondary amine reacts with a ketone or aldehyde? In the case of secondary amines, even if they form hemiaminals, there is no hydrogen atom bonded to the nitrogen atom. Therefore, the nitrogen atom and the carbon atom cannot form a double bond to produce an imine.
Instead, the reaction of a secondary amine with a carbonyl compound yields an enamine. The reaction mechanism is as follows.
It is impossible for nitrogen and carbon to form a double bond because the hydrogen atom is not attached to the nitrogen atom. Instead, the hydrogen atom (proton) bonded to the carbon atom is pulled out to produce an alkene. A compound with N-C=C structure is an enamine.
The reaction mechanism is not difficult to understand, until the reaction of the amine and the carbonyl compound produces hemiaminals. However, with amines, the synthetic reaction continues to proceed afterward. Moreover, the product depends on whether it is a primary or secondary amine.
- Reaction with primary amines: imines are formed.
- Reaction with secondary amines: enamine is formed
The reaction mechanism is complex, but try to understand what compounds you will be able to obtain.
The Hydration Reaction Produces Acetal and Hemiacetal
For compounds with carbonyl and formyl groups, there are other important synthetic reactions. These are acetal and hemiacetal. These are called hydration reactions.
In the presence of an acid catalyst, a proton is combined with the carbonyl oxygen to form a positive charge. The alcohol then attacks the carbonyl carbon, giving rise to hemiacetal. The reaction mechanism is as follows.
The reaction mechanism of hemiacetal is almost identical to the reaction mechanism we have described so far. Therefore, you will be able to understand it without any trouble.
-Acetal Is Obtained from Hemiacetal
But hemiacetal is unstable. We explained earlier that the hemiaminal, which is formed in amine synthesis, is unstable and therefore produces imines or enamines. The same is true for the hydration reaction of carbonyl compounds, and further reactions will result in products.
The hydroxy group (-OH) is able to capture a proton because of the acid-catalyzed synthetic reaction. The result is the formation of oxonium ions as the H2O is withdrawn. However, the oxonium ions are unstable intermediates and are nucleophilic attacked by alcohol. As a result, acetal is synthesized.
The mechanism of these reactions is as follows.
In other words, understand that the hydroxy group (-OH) replaces the alkoxy group (-OR).
Why is the synthesis of acetal important? Because it is a protecting group for the functional group. The synthesis of acetal is a reversible reaction. This means that it can be converted back from acetal to ketone or aldehyde.
As we’ve discussed, carbonyl carbons are highly reactive. Therefore, the addition of strongly basic reagents such as amines leads to nucleophilic addition reactions. So, if you convert it to acetal beforehand, the carbonyl group is not present and will not be nucleophilic attacked.
It can then be converted back to a compound with a carbonyl or formyl group by hydrolysis when needed.
Carbonyl Compounds Have Many Types of Synthesis
We have discussed the synthetic reactions of carbonyl compounds that do not have a leaving group. In carboxylic acid derivatives, nucleophilic acyl substitution reactions occur. On the other hand, nucleophilic addition reactions occur in carbonyl compounds without any leaving groups.
Again, the following synthetic reactions are important in these nucleophilic addition reactions
- Grignard reaction
- Synthesis of cyanohydrin
- Amine reactions: synthesis of imine or enamine
- Hydration reaction: Synthesis of acetal and hemiacetal
The reaction mechanism is the same for all of them. However, for amine reactions and hydration reactions, the compounds obtained after synthesis are unstable. Therefore, it is important to understand that the synthetic reaction proceeds further. In short, amine reactions and hydration reactions have a more complex reaction mechanism.
Carbonyl compounds are an important functional group because of the many types of reactions. Since many substituents can be synthesized from carbonyl and formyl groups, you need to understand what kind of chemical reactions take place.